The focus of our laboratory is to understand the molecular basis for the pathogenesis of mouse retroviruses. We are currently studying two animal model systems: erythroleukemia induced by the Friend spleen focus-forming virus and neurodegenerative disease induced by a variant of the Friend murine leukemia virus. Our studies have concentrated on elucidating the mechanisms by which these viruses induce their specific diseases and on characterizing the viral and host genes that are involved.The Friend spleen focus-forming virus (SFFV) induces a rapid erythroleukemia in mice due to expression of its unique envelope glycoprotein. Erythroid cells from SFFV-infected mice, in contrast to normal erythroid cells, can proliferate and differentiate in the absence of erythropoietin (Epo), the normal regulator of erythropoiesis. In an attempt to understand how SFFV alters the growth and differentiation of erythroid cells, we have been studying signal transduction pathways known to be activated by Epo to determine if SFFV exerts its biological effects by deregulating any of these pathways. We have previously shown that SFFV infection leads to the Epo-independent activation of components of the Jak-Stat and the Raf-1/MAP kinase pathways. Our current studies indicate that the virus also activates PI-3 kinase and its downstream effectors Akt and protein kinase C and that this is essential for the Epo-independent proliferation of SFFV- infected erythroid cells. Unlike Epo, SFFV preferentially activates PI 3-kinase through activation of IRS-related adaptor molecules, suggesting that it may be possible to specifically block the proliferation of SFFV-infected erythroid cells by targeting these adaptor molecules. Our studies further suggest that induction of Epo- independent differentiation of erythroid cells by SFFV requires activation of Stat proteins and that this activation is blocked in transformed cell lines derived from SFFV-infected mice. Studies are in progress to determine if this block in Stat protein activity is the result of transcriptional activation of the PU.1 gene by SFFV integration.We have also been studying a variant of the erythroleukemia-inducing Friend murine leukemia virus (MuLV) as a model for how subtle genetic changes in a retrovirus can alter its interaction with the host and result in novel biological effects. This retrovirus, designated PVC-211 MuLV, fails to cause leukemia in rodents but induces a rapid neurodegenerative disease. We previously showed that PVC-211 MuLV has undergone subtle changes in the receptor binding domain of its envelope protein which allow it to efficiently infect brain capillary endothelial cells (CEC) and that this is essential for for the neuropathogenicity of the virus. Our current studies are directed towards understanding how the envelope glycoprotein of PVC-211 MuLV interacts with receptors on brain CEC to enter the brain, determining which sequences in the virus are required for induction of neurological damage, and understanding how expression of viral proteins in brain CEC leads to degeneration of neurons. Since the unusual cell tropism of PVC-211 MuLV extends to CEC outside of the brain, we are also attempting to exploit this unique property of the virus for retroviral gene transduction targeted to the proliferating endothelium associated with developing tumors. - Animal models, retrovirus, Leukemia, spleen focus-forming virus, Signal Transduction, neuropathogenesis, PVC-, 1 MuLV, virus-cell interaction, endothelial cells, gene therapy, - Neither Human Subjects nor Human Tissues